A Broad Range of Self-Reactivity Drives Thymic Regulatory T Cell Selection to Limit Responses to Self.
Lee, Hyang-Mi 1; Bautista, Jhoanne L. 1; Scott-Browne, James 2,4; Mohan, James F. 3; Hsieh, Chyi-Song 1,*
[Article] Immunity. 37(3):475-486, September 21, 2012.

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: The degree of T cell self-reactivity considered dangerous by the immune system, thereby requiring thymic selection processes to prevent autoimmunity, is unknown. Here, we analyzed a panel of T cell receptors (TCRs) with a broad range of reactivity to ovalbumin (OVA323-339) in the rat insulin promoter (RIP)-mOVA self-antigen model for their ability to trigger thymic self-tolerance mechanisms. Thymic regulatory T (Treg) cell generation in vivo was directly correlated with in vitro TCR reactivity to OVA-peptide in a broad ~1,000-fold range. Interestingly, higher TCR affinity was associated with a larger Treg cell developmental "niche" size, even though the amount of antigen should remain constant. The TCR-reactivity threshold to elicit thymic negative selection and peripheral T cell responses was ~100-fold higher than that of Treg cell differentiation. Thus, these data suggest that the broad range of self-reactivity that elicits thymic Treg cell generation is tuned to secure peripheral tolerance to self.

Highlights: [black right pointing small triangle] Treg cell development is correlated with self-reactivity over a broad range [black right pointing small triangle] Foreign antigen reactive Treg cells may be generated by cross-reactivity to self [black right pointing small triangle] TCR affinity is correlated with the size of the Treg cell developmental "niche" [black right pointing small triangle] Peripheral responses need greater self-reactivity than thymic Treg cell selection

(C) 2012Elsevier, Inc.